Bayesian association scan reveals loci associated with human lifespan and linked biomarkers.
Aaron F McDaidPeter K JoshiEleonora PorcuAndrea KomljenovicHao LiVincenzo SorrentinoMaria LitovchenkoRoel P J BeversSina RüegerAlexandre ReymondMurielle BochudBart DeplanckeRobert W WilliamsMarc Robinson-RechaviFred PaccaudValentin RoussonJohan AuwerxJames F WilsonZoltán KutalikPublished in: Nature communications (2017)
The enormous variation in human lifespan is in part due to a myriad of sequence variants, only a few of which have been revealed to date. Since many life-shortening events are related to diseases, we developed a Mendelian randomization-based method combining 58 disease-related GWA studies to derive longevity priors for all HapMap SNPs. A Bayesian association scan, informed by these priors, for parental age of death in the UK Biobank study (n=116,279) revealed 16 independent SNPs with significant Bayes factor at a 5% false discovery rate (FDR). Eleven of them replicate (5% FDR) in five independent longevity studies combined; all but three are depleted of the life-shortening alleles in older Biobank participants. Further analysis revealed that brain expression levels of nearby genes (RBM6, SULT1A1 and CHRNA5) might be causally implicated in longevity. Gene expression and caloric restriction experiments in model organisms confirm the conserved role for RBM6 and SULT1A1 in modulating lifespan.
Keyphrases
- genome wide
- gene expression
- endothelial cells
- computed tomography
- single cell
- dna methylation
- induced pluripotent stem cells
- drosophila melanogaster
- copy number
- pluripotent stem cells
- poor prognosis
- high throughput
- physical activity
- magnetic resonance imaging
- genome wide association
- magnetic resonance
- middle aged
- cerebral ischemia
- brain injury
- cross sectional
- amino acid
- community dwelling
- multidrug resistant